Recognition and early aerobic exercise in prodrome of bipolar disorder: study protocol for a randomized controlled trial

Gui-yun Xu; Xiao-dong Chen; Ting Li; Kun Chen; Kang-guang Lin

doi:10.4103/2542-3932.198960

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STUDY PROTOCOL

Asia Pac J Clin Trials Nerv Syst Dis 2017, 2:9

Recognition and early aerobic exercise in prodrome of bipolar disorder: study protocol for a randomized controlled trial

Gui-yun Xu M.D. , Xiao-dong Chen, Ting Li, Kun Chen, Kang-guang Lin
Guangzhou Huiai Hospital, Affiliated Brain Hospital, Guangzhou Medical University, Guangzhou, Guangdong Province, China

Date of Web Publication

30-Jan-2017

Correspondence Address:
Gui-yun Xu
Guangzhou Huiai Hospital, Affiliated Brain Hospital, Guangzhou Medical University, Guangzhou, Guangdong Province
China

Source of Support: The project was funded by the National Natural Science Foundation of China (No. 81471375), the Key Medical discipline of Guangzhou, China (No. GBH2014-ZD04), and the Science and Technology Planning Project of Guangdong Province, China (No. 2011B031800154)., Conflict of Interest: None

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DOI: 10.4103/2542-3932.198960

Abstract

Background: Numerous studies have demonstrated that a long symptomatic prodromal phase (9-12 years) exists before the onset of bipolar disorder. Offspring of patients with bipolar disorders are more likely to present prodromal symptoms compared with those of healthy parents.
Methods/Design: This ongoing study is a single-center, randomized parallel-controlled trial. Eligible 120 offspring of patients with bipolar disorder, aged 10-25 years, in the prodromal stage, will be included in this study and randomized to receive psychoeducation or aerobic exercise for 3 months. The primary outcomes are changes in Clinical Global Impressions Scale scores and diagostic status from baseline to 3-month follow-up. The secondary outcomes are changes in Hamilton Depression Rating Scale scores, Young Mania Rating, Brief Psychiatric Rating Scale scores, Hamilton Anxiety Rating Scale scores, Global Assessment Scale scores from baseline to 3-month follow-up.
Discussion: The main aim of this study is to identify the prodromal stage of bipolar disorder, and to propose the effective prevention strategies for bipolar disorder. The trial results will provide important clinical evidence for the preventive effect of aerobic exercise on bipolar disorder.
Trial registration: ClinicalTrials.gov identifier NCT01863628; registered on 21 May 2013.
Ethics: This study protocol was approved by the Ethics Committee of Guangzhou Huiai Hospital, China (approval No. 2016048) and will be performed in accordance with the Declaration of Helsinki.
Informed consent: Written informed consent will be obtained from each study participant and his/her legal guardian(s) prior to enrolment.

Keywords: clinical trials; bipolar disorder; prodrome; aerobic exercise; randomized controlled trial

How to cite this article:
Xu Gy, Chen Xd, Li T, Chen K, Lin Kg. Recognition and early aerobic exercise in prodrome of bipolar disorder: study protocol for a randomized controlled trial. Asia Pac J Clin Trials Nerv Syst Dis 2017;2:9-14

How to cite this URL:
Xu Gy, Chen Xd, Li T, Chen K, Lin Kg. Recognition and early aerobic exercise in prodrome of bipolar disorder: study protocol for a randomized controlled trial. Asia Pac J Clin Trials Nerv Syst Dis [serial online] 2017 [cited 2023 Jun 6];2:9-14. Available from: https://www.actnjournal.com/text.asp?2017/2/1/9/198960

Introduction

A long symptomatic prodromal phase has been demonstrated to exist prior to the onset of bipolar disorder, lasting for 9-12 years (Egeland et al., 2000; Berk et al., 2007; Hauser et al., 2007). The prodromal stage consists of three main clusters of syndromes, including hypomania/mania symptoms, depressive symptoms, and signs of attention deficit hyperactivity disorders (Tillman et al., 2003; Correll et al., 2007; Dutta et al., 2007; Mantere et al., 2008). Of the hypomania/mania symptoms, decreased sleep, elevated mood, irritability, mood lability, increased energy, and psychomotor agitation are present most frequently. The prodromal depressive symptoms are reported to be depressed mood, anhedonia, insomnia, and feelings of worthlessness. Among patients with bipolar disorders, 22.5% are comorbid with pediatric attention deficit hyperactivity disorder (ADHD). In addition, some symptoms are considered non-specific, such as decreased function, anger outburst, social isolation, and anxiety (Egeland et al., 2000).

Offspring of parents with bipolar disorders are more likely to present prodromal symptoms compared with offspring of healthy parents. In a 10-year longitudinal study using 55 prodromal symptoms checklist, Egeland et al. (2003) found that offspring of parents with bipolar disorder were considered at higher risk compared to children of healthy parents (38% vs. 17%). In a 15-year follow-up study, Duffy et al. (2009) found that 32.7% of offspring (age 8-25 years) of parents with bipolar disorder met the criteria of major mood episode.

Objectives

The aims of this study are (1) to prospectively identify the prodromal stage of bipolar disorder, (2) to conduct a randomized controlled trial to study delayed effects of aerobic exercise on prodromal symptoms of bipolar disorder to the extent of significantly impaired function in bipolar disorder.

Methods/Design

Study design

Prospective, single-center, assessor-blinded, randomized parallel-controlled trial ([Figure 1]).

Figure 1: Flow chart of the trial.

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Study setting

Guangzhou Huiai Hospital, Affiliated Brain Hospital, Guangzhou Medical University, Guangzhou, Guangdong Province, China.

Study procedure

The study will consist of two phases: 1-week screening period and a 3-month randomized controlled trial. During the screening period, offspring of parents with bipolar disorder will undergo systematically clinical evaluations using the Structured Clinical Interview for DSM-IV Axis I Disorders (SCID I) (First et al., 1997) by one senior psychiatrist. Screening will be performed in the offspring of patients with bipolar disorder by assessment via psychiatric diagnosis using the Kiddie Schedule of Affective Disorders and Schizophrenia Present and Lifetime Version (K-SADS-PL) (Kaufman et al., 1997) by the senior psychiatrist and prodromal symptoms will be evaluated using the Prodromal Symptom Checklist for Bipolar Disorder, and clinical symptoms will be further evaluated using psychiatric assessment scales, neuropsychological tests, magnetic resonance imaging (MRI). During the 3-month trial period, the offspring who meet the inclusion criteria will be randomly assigned to receive treatment of aerobic exercise or psychoeducation. Psychiatrists are scheduled to assess clinical symptoms and treatment outcome at baseline and after 3-month intervention.

Study participants

It is expected that 120 offspring of parents with bipolar disorder aged 10-25 years, meeting the inclusion of prodromal stage, will be included in the study. All of the offspring will undertake assessment of the Kiddie Sads Present and Lifetime Version (K-SADS-PL; Kaufman et al., 1997), and a 70 checklist items of potential prodromal symptoms suggested by us as well as by Dr. Correll et al. (2007). The parents of these offspring are to have DSM-IV (Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition)-defined bipolar disorder (bipolar I or II), confirmed by the Chinese version of Structured Clinical interview for DSM-IV-TR Axis I Disorders patient edition (SCID-I/P) (First et al., 2002; Kessler et al., 2005). The offsprings will be recruited through the referrals by their parents who will receive psychiatric services in Guangzhou Huiai Hospital, China.

Inclusion criteria

At least one biological parent diagnosed as having bipolar disorder (bipolar I or II)
Have at least one of the following symptoms: i) two or more DSM-IV defined hypomania/mania symptoms, lasting for at least 4 days; ii) two or more DSM-IV defined major depressive symptoms, lasting for 1 week; iii) at least one of the psychotic symptoms, lasting at least 10 minutes for each manifestation, and 2-7 manifestations a week for at least 3 months, including: ideas of reference, odd ideas, odd belief, unusual perceptual experiences, bizarre thought or speech, grandiosity, suspicious ideas, paranoid idea, odd mannerisms, hallucination, disorganized/catatonic behavior; iv) two or more of the DSM-IV defined ADHD symptoms; and there must be clear evidence of clinically significant impairment in social, academic, or occupational functioning due to ADHD symptoms; v) two or more anxiety or panic symptoms, lasting at least 1 month, and resulting in social function impairment.

Exclusion criteria

DSM-IV defined Axis I disorders
Serious physical medical illness
Mental retardation
A recent history of/current treatment with antipsychotic drugs
Unable to complete neuropsychological tests due to physical conditions
Pregnancy and lactation
Are currently receiving thyroxine therapy in the last 3 months or taking hormone therapy

Randomization

Subjects are assigned to one of the two intervention groups with a 1:1 allocation based on a sequence generated by a computer equipped with SPSS 18.0 software (SPSS, Chicago, IL, USA). Clinicians involved in the study procedure are blinded to this assignment by using numbered and sealed envelopes.

Blinding

All investigators who administer the outcome measurement questionnaire and statistician will be blinded to the treatment allocation, while the practitioners and subjects will be aware of the allocation arm.

Intervention

The aerobic exercise will include cycling, jogging, table tennis, and playing badminton for 40-60 minutes at least 3 days a week for 3 months. In each exercise, the participants are supposed to exercise to the extent of getting sweaty. Before and after exercise, the heart rate, calories and lasting time recorded by sports watch every exercise and rest will be measured in the participants. In the psychoeducation group, participants will receive general psychoeducation for six times, including delivering knowledge on symptoms, bipolar disorder and other mental disorders, discussion of the suffering mental difficulties, and general coping techniques. Of course, the participants in the psychoeducation group will be ask to wear sports watch to measure the heart rate, calories every day.

Outcome measures

Primary outcome measures

Change in Clinical Global Impressions Scale (CGI) scores from baseline to post 3-month intervention after intervention. CGI (Spearing et al., 1997) is used to assess the patient's global function prior to and after initiating a study intervention. The CGI provides an overall clinician-determined summary measure, taking into account all available information, including a knowledge of the patient's history, psychosocial circumstances, symptoms, behavior, and the impact of the symptoms on the patient's function.
Change in diagnostic status from baseline to post 3-month intervention. Diagnostic status is observed to assess with DSM-IV-TR by a senior psychiatrist whether participants are in the defined prodromal stage of bipolar disorder or full bipolar disorder and other mental disorder.

Secondary outcome measures

Change in Hamilton Depression Rating Scale (HDRS) scores from baseline to post 3-month intervention. HDRS (Williams, 1988) is used to assess the depressive symptoms.
Change in Young Mania Rating Scale (YMRS) scores from baseline post 3-month intervention. YMRS (Young et al., 1978) is used to assess hypomania/mania symptoms.
Change in Brief Psychiatric Rating Scale (BPRS) scores from baseline to post 3-month intervention. BPRS (Tool, 1988) is used to assess psychotic symptoms.
Change in Hamilton Rating Scale for Anxiety (HAM-A) scores from baseline to post 3-month intervention. HAM-A (Hamilton, 1960) is used to assess anxious symptoms.
Change in Global Assessment Scale (GAS) scores from baseline to post 3-month intervention. GAS (Endicott et al., 1976) is a numeric scale (1 through 100) used by mental health clinicians to rate the general function of children.

Other outcome measures

Change in neuropsychological performance from baseline to post 3-month intervention. Neuropsychological performance is valuated with the MATRICS Consensus Cognitive Battery (MCCB), Test of Non-verbal Intelligence (TONI-3), and Stroop Color-Word Test. The MATRICS Consensus Cognitive Battery (MCCB) (Kern et al., 2008; Nuechterlein et al., 2008), developed by the National Institute of Mental Health (NIMH) Measurement and Treatment Research to Improve Cognition in Schizophrenia (MATRICS) initiative, has been recommended as the standard battery for clinical trials of cognition-enhancing interventions for schizophrenia as well as bipolar disorders. TONI-3 (Brown et al., 1997) is used as language free intelligence measure which also helps in the assessment of aptitude, abstract reasoning and problem solving. Stroop Color-Word Test involves naming the sensory color in which a word is printed (Stroop, 1935). When the words conflict with color names, the rate at which sensory print colors can be named is slowed dramatically, whereas the rate at which the words can be read is almost completely unaffected by the color in which they are printed.
Change in functional magnetic resonance imaging from baseline to post 3-month intervention. Functional magnetic resonance imaging or functional MRI (fMRI) is an magnetic resonance imaging procedure that measures brain activity by detecting associated changes in blood flow.
Change in 70 prodromal symptoms checklist for bipolar disorder from baseline to post 3-month intervention. The instrument consists of 70 items is used to assess different sorts of symptoms based on the researchers' clinical experiences and current literatures.

All outcome measures in the trial are summarized in [Table 1].

Table 1: Timing of data collection, interventions, and outcome evaluations in the trial

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Data collection and management

Paper based case report forms (CRF) will be used for documentation. Entries will be transferred into an electronic format using a double-data entry strategy by trained professional staff. The accuracy of the information will be verified when each patient are followed up. For confidentiality, all data collected from patients will be assigned a study serial number in the database and de-identified. Electronic data will be preserved in a password-protected computer and managed by a professional.

Sample size

Base on a previous related study (Duan et al., 2015), with a type I error of 5% (α = 0.05) and 90% power (β = 0.10), we anticipate that a sample size of 120 will be needed when considering a 20% drop-out rate.

Statistical analysis

Continuous measurements will be expressed as means and standard deviations (SD) and categorical measurements will be summarized using numbers and percentages.

Statistical analysis of data will be performed using SPSS18.0 software. For statistical description, continuous variables will be presented using the mean ± SD for normal distribution, and median and interquartile range for non-normal distribution. Categorical variables will be presented using proportions. In order to compare the outcome measures between groups, the Student's t-test or Mann-Whitney U test will be used for continuous variables and the chi-square or Fisher's exact test will be used for categorical variables. Paired t-test will be used for intra-group comparison. A P value < 0.05 was considered statistically significant.

Discussion

Bipolar disorder is one of the most common recurrent mental illnesses. The mean age for the onset of bipolar disorder is approximately 20 years old with peak at age of 15-19 years. Existing evidence has shown that the first symptom of bipolar disorder appears as early as 3 years old (Berk et al., 2007), however, a proper diagnosis and treatment for bipolar disorder is delayed to ~16 years old (Hauser et al., 2007). As such, it is important to recognize the prodrome of bipolar disorder and seek an early intervention approach for preventing or postponing the onset of bipolar disorder.

This study is the first to perform aerobic exercise in the offspring of parents with bipolar disorder, and the design of a randomized, controlled, parallel-group clinical trial is used to assess the effectiveness of aerobic exercise for preventing or delaying the onset of bipolar disorder.

The study will contribute to clinical practice by providing evidence that will help guide decisions about the appropriate early intervention of the prodrome in bipolar disorder and also may contribute a solution to the difficult problem of the recognition of the prodrome in bipolar disorder.

Trial Status

Recruitment is ongoing at the time of submission.[24]

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Declaration of patient consent
The authors certify that they will obtain all appropriate patient consent forms. In the form the patients will give their consent for their images and other clinical information to be reported in the journal. The patients understand that their names and initials will not be published and due efforts will be made to conceal their identity, but anonymity cannot be guaranteed.
Conflicts of interest
None declared.
Author contributions
Design of study protocol: GYX, KGL and XDC. Data collection and processing: KC and TL. All authors approved the final version of the manuscript.
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Peer review
This paper was double-blinded and stringently reviewed by international expert reviewers.